Diaryl-enynes

ABSTRACT

Provided, among other things, is a compound of Formula I:                    
     wherein: 
     Ar 1  and Ar 2  are independently selected aryl groups, optionally substituted with up to five substituents independently selected from the group consisting of 
     alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl, heterocycloalkyl-substituted alkoxy, heterocycloalkyloxy-substituted alkoxy, thioaryl, aralkylthio, thioarylalkyl, aralkylthioalkyl, halo, NO 2 , CF 3 , CN, OH, alkylenedioxy, SO 2 NRR′, NRR′, CO 2 R (where R and R′ are independently selected from the group consisting of H and alkyl), and a second aryl group, which may be substituted as above; 
     R 1  is selected from the group consisting of H and alkyl; 
     R 2  is selected from the group consisting of H, alkyl and benzyl; 
     R 3  is selected from the group consisting of CO 2 R, CONRR′, CONH(OH), COSR, SO 2 NRR′, PO(OR)(OR′) and tetrazolyl, wherein R and R′ are independently selected from the group consisting of H and alkyl; 
     and a salt, solvate or hydrate thereof.

This application claims the benifit of Provisional Application No.60/162,986, filed Nov. 1, 1999.

The present invention relates to a class of diaryl-enynes, topharmaceutical compositions containing them and to methods of treatingneurological and neuropsychiatric disorders using such compounds.

BACKGROUND OF THE INVENTION

Synaptic transmission is a complex form of intercellular communicationthat involves a considerable array of specialized structures in both thepre- and post-synaptic terminal and surrounding glial cells (Kanner andSchuldiner, CRC Critical Reviews in Biochemistry, 22, 1987:1032).Transporters sequester neurotransmitter from the synapse, therebyregulating the concentration of neurotransmitter in the synapse, as wellas its duration therein, which together influence the magnitude ofsynaptic transmission. Further, by preventing the spread of transmitterto neighbouring synapses, transporters maintain the fidelity of synaptictransmission. Lastly, by sequestering released transmitter into thepresynaptic terminal, transporters allow for transmitter reutilization.

Neurotransmitter transport is dependent upon extracellular sodium andthe voltage difference across the membrane; under conditions of intenseneuronal firing, as, for example, during a seizure, transporters canfunction in reverse, releasing neurotransmitter in a calcium-independentnon-exocytotic manner (Attwell et al., Neuron, 11, 1993:401-407).Pharmacologic modulation of neurotransmitter transporters thus providesa means for modifying synaptic activity, which provides useful therapyfor the treatment of neurological and psychiatric disturbances.

The amino acid glycine is a major neurotransmitter in the mammaliancentral nervous system, functioning at both inhibitory and excitatorysynapses. By nervous system, both the central and peripheral portions ofthe nervous system are intended. These distinct functions of glycine aremediated by two different types of receptor, each of which is associatedwith a different class of glycine transporter. The inhibitory actions ofglycine are mediated by glycine receptors that are sensitive to theconvulsant alkaloid strychnine, and are thus referred to as“strychnine-sensitive”. Such receptors contain an intrinsic chloridechannel that is opened upon binding of glycine to the receptor; byincreasing chloride conductance, the threshold for firing of an actionpotential is increased. Strychnine-sensitive glycine receptors are foundpredominantly in the spinal cord and brainstem, and pharmacologicalagents that enhance the activation of such receptors will thus increaseinhibitory neurotransmission in these regions.

Glycine also functions in excitatory transmission by modulating theactions of glutamate, the major excitatory neurotransmitter in thecentral nervous system (Johnson and Ascher, Nature, 325, 1987:529-531;Fletcher et al., Glycine Transmission, Otterson and Storm-Mathisen,eds., 1990:193-219). Specifically, glycine is an obligatory co-agonistat the class of glutamate receptor termed N-methyl-D-aspartate (NMDA)receptor. Activation of NMDA receptors increases sodium and calciumconductance, which depolarizes the neuron, thereby increasing thelikelihood that it will fire an action potential.

NMDA receptors in the hippocampal region of the brain play an importantrole in a model of synaptic plasticity known as long-term potentiation(LTP), which is integral in certain types of learning and memory (Hebb,D. O (1949) The Organization of Behavior; Wiley, N.Y.; Bliss andCollingridge (1993) Nature 361: 31-39; Morris et al. (1986) Nature 319:774-776). Enhanced expression of selected NMDA receptor sub-units intransgenic mice results in increased NMDA-receptor-mediated currents,enhanced LTP, and better performance in some tests of learning andmemory (Tang et al. (999) Nature 401: 63).

Conversely, decreased expression of selected NMDA receptor sub-units intransgenic mice produces behaviors similar to pharmacologically-inducedanimal models of schizophrenia, including increased locomotion,increased stereotypy, and deficits in social/sexual interactions (Mohnet al. (1999) Cell 98:427-436). These aberrant behaviors can beameliorated using the antipsychotics haloperidol and clozapine.

NMDA receptors are widely distributed throughout the brain, with aparticularly high density in the cerebral cortex and hippocampalformation.

Molecular cloning has revealed the existence in mammalian brains twoclasses of glycine transporters, termed GlyT-1 and GlyT-2. GlyT-1 isfound throughout the brain and spinal cord, and it has been suggestedthat its distribution corresponds to that of glutamatergic pathways andNMDA receptors (Smith, et al., Neuron, 8, 1992:927-935). Molecularcloning has further revealed the existence of three variants of GlyT-1,termed GlyT-1a, GlyT-1b and GlyT-1c. Two of these variants (1a and 1b)are found in rodents, each of which displays a unique distribution inthe brain and peripheral tissues (Borowsky et al., Neuron, 10,1993:851-863; Adams et al., J. Neuroscience, 15, 1995:2524-2532). Thethird variant, 1c, has only been detected in human tissues (Kim, et al.,Molecular Pharmacology, 45, 1994:608-617). These variants arise bydifferential splicing and exon usage, and differ in their N-terminalregions. GlyT-2, in contrast, is found predominantly in the brain stemand spinal cord, and its distribution corresponds closely to that ofstrychnine-sensitive glycine receptors (Liu et al., J. BiologicalChemistry, 268, 1993:22802-22808; Jursky and Nelson, J. Neurochemistry,64, 1995:1026-1033). Another distinguishing feature of glycine transportmediated by GlyT-2 is that it is not inhibited by sarcosine as is thecase for glycine transport mediated by GlyT-1. These data are consistentwith the view that, by regulating the synaptic levels of glycine, GlyT-1and GlyT-2 selectively influence the activity of NMDA receptors andstrychnine-sensitive glycine receptors, respectively.

Compounds which inhibit or activate glycine transporters would thus beexpected to alter receptor function and, thus, provide therapeuticbenefits in a variety of disease states.

For example, compounds which inhibit GlyT-1 mediated glycine transportwill increase glycine concentrations at NMDA receptors, which receptorsare located in the forebrain, among other locations. This concentrationincrease elevates the activity of NMDA receptors, thereby alleviatingschizophrenia and enhancing cognitive function. Alternatively, compoundsthat interact directly with the glycine receptor component of the NMDAreceptor can have the same or similar effects as increasing ordecreasing the availability of extracellular glycine caused byinhibiting or enhancing GlyT-1 activity, respectively. See, for example,Pitkänen et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels et al.,Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J.Neurosci., 16, 1561-1569 (1996).

The present invention provides compounds that affect glycine transport.The invention also provides compositions useful to treat medicalconditions for which a glycine transport modulator, and particularlyglycine uptake inhibitors, are indicated.

SUMMARY OF THE INVENTION

According to one aspect of the invention, there are provided compoundsof Formula I:

wherein:

Ar₁ and Ar₂ are independently selected aryl groups, optionallysubstituted with up to five substituents independently selected from thegroup consisting of alkyl, alkoxy, cycloalkyl, cycloalkyloxy,heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl,aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl,cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy,cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl,heterocycloalkyloxy-substituted alkyl heterocycloalkyl-substitutedalkoxy, heterocycloalkyloxy-substituted alkoxy, thioaryl, aralkylthio,thioaryl-alky, aralkylthioalkyl, halo, NO₂, CF₃, CN, OH, alkylenedioxy,SO₂NRR′, NRR′, CO₂R (where R and R′ are independently selected from thegroup consisting of H and alkyl) and a second aryl group, which may besubstituted as above;

R₁ is selected from the group consisting of H and alkyl;

R₂ is selected from the group consisting of H, alkyl and benzyl;

R₃ is selected from the group consisting of CO₂R, CONRR′, CONH(OH),COSR, SO₂NRR′, PO(OR)(OR′) and tetrazolyl, wherein R and R′ areindependently selected from the group consisting of H and alkyl;

and a salt, solvate or hydrate thereof.

It has been found that compounds of Formula I inhibit glycine transport(or reuptake) via the GlyT-1 transporter, or are precursors (forexample, pro-drugs) of such compounds and, thus, are useful in thetreatment of schizophrenia, as well as other CNS-related disorders suchas cognitive dysfunction, dementia (including that related toAlzheimer's disease), attention deficit disorder and depression.

According to another aspect of the invention, there is provided apharmaceutical composition comprising a compound of Formula I in anamount effective to inhibit glycine transport, and a pharmaceuticallyacceptable carrier.

In another aspect of the invention there are provided compositionscontaining the present compounds in amounts for pharmaceutical use totreat medical conditions for which a glycine transport inhibitor isindicated. Preferred are those compositions containing compounds usefulin the treatment of medical conditions for which GlyT-1-mediatedinhibition of glycine transport is needed, such as the treatment ofschizophrenia or cognitive dysfunction.

Definitions

The term aryl as used herein means a monocyclic aromatic group such asphenyl, pyridyl, furyl, thienyl, and the like, or a benzo-fused aromaticgroup such as naphthyl, indanyl, quinolinyl, fluorenyl and the like.

The term alkyl as used herein means straight- and branched-chain alkylradicals containing from one to six carbon atoms and includes methyl,ethyl and the like.

The term cycloalkyl as used herein means a carbocyclic ring containingfrom three to eight carbon atoms and includes cyclopropyl, cyclohexyland the like. Similarly, the term “cycloalkyloxy” refers to such acarbocycle that is coupled through an oxygen to another group, andincludes cyclohexyloxy and the like.

The term heterocycloalkyl as used herein means a three- toeight-membered ring containing up to two heteroatoms selected from thegroup consisting of N, S and O, and includes piperidinyl, piperazinyl,thiopyranyl and the like. Such rings coupled to another group through anoxygen, such as piperidinyloxy and the like, are referred to asheterocycloalkyloxy groups.

The terms aralkyl, aryloxyalkyl, aralkyloxy and aryloxyalkoxy as usedherein refer to an alkyl or alkoxy radical substituted with an aryl oraryloxy group and includes benzyl, phenethyl, benzyloxy, 2-phenoxyethyland the like. Similarly, the terms cycloalkyl-substituted alkyl,cycloalkyl-substituted alkoxy, heterocycloalkyl-substituted alkyl andheterocycloalkyl-substituted alkoxy mean groups such as2-cyclohexyl-ethyl and the like. Further, substituents in which an alkylor alkoxy group is substituted by another group through a bridgingoxygen, are groups referred to herein as cycloalkyloxy-substitutedalkyl, cycloalkyloxy-substituted alkoxy, heterocycloalkyloxy-substitutedalkyl and heterocycloalkyloxy-substituted alkoxy.

The terms alkylene (e.g., —CH2—CH2—), alkenylene (e.g., —CH═CH—) andalkynylene (e.g., —CH≡CH—) as used herein means straight- andbranched-chain bivalent radicals containing from one to six carbonatoms, such as methylene, ethylene, vinylene, propenylene andethynylene.

The terms alkylene (e.g., —CH2—CH2—), alkenylene (e.g., —CH═CH—) andalkynylene (e.g., —CH≡CH—) as used herein means straight- andbranched-chain bivalent radicals containing from one to six carbonatoms, such as methylene, ethylene, vinylene, propenylene andethynylene.

The term alkoxy as used herein means straight- and branched-chain alkoxyradicals containing from one to six carbon atoms and includes methoxy,ethoxy and the like.

The term thioalkyl as used herein means straight- and branched-chainalkyl radicals containing from one to six carbon atoms and includesthiomethyl (CH3—S—), thiopropyl and the like.

The term thioaryl refers to an aryl group that is bridged to anothergroup through a sulfur. Similarly, a thioarylalkyl group is a thioarylgroup bridged to another group through an alkylene group. Also, anaralkythio group is an aralkyl group, such as benzyl, which is bridgedto another group through a sulfur atom. Further, an arylalkylthioalkylgroup is an arylalkyl group that is bridged to another group through athioalkyl group.

The term alkanoyl as used herein means straight- and branched-chainradicals containing from one to six carbon atoms and includes acetyl,propionyl and the like.

The term halo as used herein means halogen and includes fluoro, chloro,bromo and the like. The term haloalkyl refers to an alkyl groupsubstituted by one or more independently selected halo atoms, such as—CF3. Similarly, the term haloalkoxy refers to an alkoxy groupsubstituted by one or more independently selected halo atoms, such as—OCF3.

The term alkylenedioxy refers to a group of the formula —O—(CH2)n—O—, inwhich the terminal oxygen typically are fused to atoms on an aryl groupto form a bicyclic ring system, and includes methylenedioxy,ethylenedioxy and the like.

The term hetero atom as used herein means atoms other carbon andincludes N, S and O.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The geometry about the double bond of the compounds of Formula I is asdrawn. That is, group Ar₂ and the carbon atom to which group R₁ isattached are cis to each other.

Compounds of Formula I include those in which Ar₁ and Ar₂ are,independently, optionally-substituted aryl groups.

Substitution sites on rings Ar₁ and Ar₂ will be limited in practice tothe carbon atoms on the ring not bound to the core of the molecule. Forexample, a benzene ring can be substituted with up to 5 substituents;pyridine and pyran can accommodate up to 4 substituents pyrole furan andthiophene can accommodate up to 3 substituents; imidazole 2 substituentsand triazole can accommodate only one substituent.

In embodiments of the invention Arl is an optionally monocyclic aromaticgroup such as benzene, pyridine, pyran, thiophene, furan, pyrole,imidazole and triazole. Ar₁ suitably accomodates 1, 2 or 3 substituentson the aromatic ring and these can be chosen from such groups as alkyl,alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl,heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy,aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl,cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy,cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl,heterocycloalkyloxy-substituted alkyl heterocycloalkyl-substitutedalkoxy, heterocycloalkyloxy-substituted alkoxy, thioaryl, aralkylthio,thioaryl-alky, halo, NO₂, CF₃, CN, OH, methylenedioxy, ethylenedioxy,SO₂NRR′, NRR′, CO₂R (where R and R′ are independently selected from thegroup consisting of H and alkyl) or an aryl group optionally substitutedas stated above.

In suitable embodiments of the invention, Ar₁ is selected from benzene,pyridine, pyran, thiophene, furan and pyrole, optionally substitutedwith 1, 2 or 3 substituents selected from halo, NO2, CF3, CN, OH, alkyl,alkoxy, aryl, aralkyl, and R″(X)n. where n is 0 or 1;X is CH₂ or aheteroatom; and R″ is H, alkyl or aryl substituted optionally with up tothree substituents selected from alkyl, halo, NO₂, CF₃, CN, OH, SO₂NRR′,NRR′, and CO₂R (where R and R′ are independently selected from the groupconsisting of H and alkyl).

In particular embodiments, Ar₁ is phenyl optionally substituted with 1,2 or 3 substituents selected from halo, NO2, CF3, CN, OH, and R″(X)_(n.)where n is 0 or 1; X is CH₂ O, S, or NR; and R″ is H, alkyl or arylsubstituted optionally with up to three substituents selectedindependently from alkyl, halo, NO₂, CF₃, CN, OH, SO₂NRR′, NRR′, CO₂R(where R and R′ are independently selected from the group consisting ofH and alkyl).

In more particular embodiments, Ar₁ is phenyl optionally substitutedwith 1 or 2 substituents selected from alkyl, thioalkyl, alkoxy, halo,haloalkyl, haloalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, and substituted or unsubstituted aralkyl.

In specific embodiments, Ar₁ is mono-substituted phenyl where thesubstituent is located at the 4 position and is selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, 3-furyl, and 3-thienyl.

In other embodiments, Ar₁ is an optionally substituted benzofusedaromatic group such as naphthalene, quinoline, indole, anthracene,fluorenyl, alkylenedioxyphenyl and the like, where the substituents canbe selected from halo, NO2, CF3, CN, OH, alkyl, alkoxy, aryl, aralkyl,and R″(X)_(n.) where n is 0 or 1; X is CH₂ or a heteroatom; and R″ is H,alkyl or aryl substituted optionally with up to three substituentsselected from alkyl, halo, NO₂, CF₃, CN, OH, SO₂NRR′, NRR′, CO₂R (whereR and R′ are independently selected from the group consisting of H andalkyl).

In particular embodiments, Ar₁ can be naphthyl, quinolinyl, indanyl, oralkylenedioxyphenyl, optionally substituted with 1 or 2 substituentsselected from alkyl, alkoxy, thioalkyl and aryl.

In a specific embodiment, Ar₁ is selected from unsubstituted naphthaleneand methylenedioxyphenyl.

In other embodiments of the invention, Ar₂ is an optionally substitutedaryl, where aryl, is a monocyclic aromatic group such as benzene,pyridine, pyran, furan, thiophene, pyrrolidine and the like, or is abenzofused aromatic ring system such as naphthalene, quinoline, indole,anthracene, fluorenyl, alkylenedioxyphenyl and the like. Either 1, 2, or3 substituents may be present, and these may be independently selectedfrom halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.

In a particular embodiment, A is a monocyclic aromatic ring bearing upto three substituents selected independently from halo, haloalkyl,alkyl, haloalkoxy, and alkoxy. In more particular embodiments, A isselected from mono or di-substituted phenyl, where the substituents areselected from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.

In specific embodiments, Ar₂ is a phenyl group that is eitherunsubstituted or has one substituent selected from halo and alkoxy.

In more specific embodiments, Ar₂ is selected from unsubstituted or monosubstituted phenyl, where the substituent is selected from chloro andflouro.

In other embodiments of the invention, R₃ is selected from the groupconsisting of —CO₂R, —CONRR′, —CONH(OH), —COSR, —SO₂NRR′, —PO(OR)(OR′)and tetrazolyl wherein R and R′ are independently selected from thegroup consisting of H and alkyl.

In particular embodiments, R₃ is COOR. In preferred embodiments of theinvention, R₃ is COOH.

The compounds of Formula I include those in which R1 is selected fromthe group consisting of H and alkyl. Preferably, R₁ is H.

The compounds of Formula I include those in which R₂ is selected fromthe group consisting of H, alkyl and benzyl. Suitably, R₂ alkyl; morepreferably, R₂ is methyl.

In preferred embodiments, compounds of Formula I are those in which R₁is H, R₂ is methyl, R₃ is COOH. In this context, Ar₁ and Ar₂ aredesirably substituted or unsubstituted phenyl. Preferably, Ar₁ is eitherphenyl or 4-(substituted)-phenyl. When substituted, Ar₁ is desirably a4-(alkyl)-phenyl group, particularly where the alkyl group is astraight-chain alkyl group, including 4-isopropyl-phenyl,4-ethyl-phenyl, and 4-n-propyl-phenyl. Either in combination therewithor independently thereof, Ar₂ is preferably is chloro or fluorosubstituted phenyl.

In another preferred embodiment, R₁ is H, R₂ is methyl, R₃ is COOH, Ar₂is unsubstituted phenyl and Ar₁ is 4-alkyl substituted phenyl wherealkyl is C₁₋₄ straight chain.

In another preferred embodiment R₁ is H, R₂ is methyl, R₃ is COOH, Ar₂is 2-chlorophenyl and Ar₁ is 4-alkyl phenyl where the alkyl substituentis selected from ethyl and propyl.

In another preferred embodiment of the invention R₁ is H, R₂ is methyl,R₃ is COOH, Ar₁ is naphthyl, especially 2-naphthyl, and Ar₂ is phenyl.

In yet another preferred embodiment of the invention R₁ is H, R₂ ismethyl, R₃ is COOH, Ar₁ is 3,4-methylenedioxyphenyl and Ar₂ is3-fluoro-phenyl.

In still another preferred embodiment of the invention R₁ is H, R₂ ismethyl, R₃ is COOH, Ar₂ is phenyl and Ar₁ is an optionally substitutedaryl substituted phenyl.

In a more preferred embodiment of the invention R₁ is H, R₂ is methyl,R₃ is COOH, Ar₂ is phenyl and Ar₁ is phenyl substituted by a 5-memberedheteroaryl that is optionally substituted.

In a most preferred embodiment of the invention R₁ is H, R₂ is methyl,R₃ is COOH, Ar₂ is phenyl and Ar₁ is 4-(3-furyl)phenyl.

Specific compounds of Formula I include:

N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(2-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(2,4-Difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(3-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(3-Phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,

N-(5-(3,5-Bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(3,5-Diphenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-diphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-^(n)propylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-^(n)butylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-^(n)pentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(3-Phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(3-Phenyl-5-(3-thiophene)-2-penten-4-yn-1-yl)-sarcosine

N-(3-Phenyl-5-(4-tbutylphenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-(3-furyl)-phenyl)-3-phenyl-2-penten-4yn-1-yl)-sarcosine

N-(5-(4-(3-thiophene)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-t-Butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-t-Butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-t-Butylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(3,4-Methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

N-(5-(4-Propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

Compounds of Formula I can be considered to be amino acids orderivatives thereof. Compounds which contain, instead of a carboxylategroup, a “carboxylate equivalent” group, such as hydroxamic acids,phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids,amides or tetrazoles, are also considered embodiments of the presentinvention.

In another embodiment of the invention, the compound of Formula I isprovided in labeled form, such as radiolabeled form (e.g. labeled byincorporation within its structure ³H or ¹⁴C or by conjugation to ¹²⁵I).In a preferred aspect of the invention, such compounds, which bindpreferentially to GlyT-1, can be used to identify GlyT-1 receptorligands by techniques common in the art. This can be achieved byincubating the receptor or tissue in the presence of a ligand candidateand then incubating the resulting preparation with an equimolar amountof radiolabeled compound of the invention. GlyT-1 receptor ligands arethus revealed as those that significantly occupy the GlyT-1 site andprevent binding of the radiolabeled compound of the present invention.Alternatively, GlyT-1 receptor ligand candidates may be identified byfirst incubating a radiolabeled form of a compound of the invention thenincubating the resulting preparation in the presence of the candidateligand. A more potent GlyT-1 receptor ligand will, at equimolarconcentration, displace the radiolabeled compound of the invention.

Acid addition salts of the compounds of Formula I are most suitablyformed from pharmaceutically acceptable acids, and include for examplethose formed with inorganic acids e.g. hydrochloric, sulphuric orphosphoric acids and organic acids e.g. succinic, maleic, acetic orfumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalatesmay be used for example in the isolation of compounds of Formula I forlaboratory use, or for subsequent conversion to a pharmaceuticallyacceptable acid addition salt. Also included within the scope of theinvention are base addition salts (such as sodium, potassium andammonium salts), solvates and hydrates of compounds of the invention.Base salts are preferred and sodium and potassium salts are especiallypreferred.

The conversion of a given compound salt to a desired compound salt isachieved by applying standard techniques, well known to one skilled inthe art.

The compounds of the present invention can be prepared by processesanalogous to those established in the art. For example, compounds ofFormula I are readily prepared by the method shown in Scheme 1, below.Intermediate C was prepared according to the method of Trost (Trost, B.M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruther, G. J. Am. Chem. Soc.1997, 119, 698-708; Trost, B. M.; Hachiya, I.; McIntosh, M. C.Tetrahedron Lett. 1998, 39, 6445-6448) by coupling an arylpropiolicester such as A with trimethylsilylacetylene B in the presence ofpalladium acetate and tris(2,6-dimethoxyphenyl)phosphine. Reduction ofthe ester to the alcohol, and treatment with N-Bromosuccinimide gavebromide D. Treatment of D with a sarcosine ester (such as tbutylsarcosine) in the presence of base gave the intermediate sarcosinederivative E. Removal of the trimethylsilyl group (for example, bytreatment with potassium carbonate in methanol), followed byintroduction of the second aryl group by a Sonogashira coupling(Sonogashira, K.; Yohda, Y. and Hagihara, N.; Tetrahedron Lett., 1975,4467), gave the diaryl species G which, upon deprotection with, forexample, formic acid, gave the final product H.

This route is an attractive one for the parallel synthesis of a seriesof related compounds in which group Ar₂ is constant, but group Ar₁represents a number of different aryl groups. Common intermediate F canbe prepared in bulk, and simply treated with the appropriate aryliodideunder Sonogashira conditions to yield the desired products.

Alternatively, such compounds may also be prepared according to theroute shown in Scheme 2, below. This route complements that shown above,in that it allows the parallel synthesis of a series of relatedcompounds in which group Ar₁ is constant, but group Ar₂ represents anumber of different aryl groups. In this case, common intermediate L canbe prepared in bulk, and simply treated with the appropriatearylpropiolic ester O (readily accessible from aryliodide M by treatmentwith propiolic ester N in the presence of Cul and Pd(PPh₃)₄), under theconditions outlined above, to yield, after deprotection, products H.

To prepare compounds in which Ar₁ is Aryl-substituted phenyl(Ar₃-phenyl), the following synthesis (Scheme 3) is useful. IntermediateF can be prepared according to Scheme 1, then coupled tobromoiodobenzene via Sonogashira coupling to yield species S. Thearyliodide of species S can then be reacted with a boronic acid(Ar₃-boronic acid) under Suzuki coupling conditions to give intermediateG′. (G′ is equivalent to G, Scheme 1, Where Ar₁ is Ar₃-phenyl). G′ canthen be deprotected as in Scheme 1 to give H′.

Compounds which inhibit GlyT-1 mediated glycine transport will increaseglycine concentrations at NMDA receptors, which receptors are located inthe forebrain, among other locations. This concentration increaseelevates the activity of NMDA receptors, thereby alleviatingschizophrenia and enhancing cognitive function. Alternatively, compoundsthat interact directly with the glycine receptor component of the NMDAreceptor can have the same or similar effects as increasing ordecreasing the availability of extracellular glycine caused byinhibiting or enhancing GlyT-1 activity, respectively. See, for example,Pitkadnen et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels etal., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J.Neurosci., 16, 1561-1569 (1996).

The compounds of the invention are, for instance, administered orally,sublingually, rectally, nasally, vaginally, topically (including the useof a patch or other transdermal delivery device), by pulmonary route byuse of an aerosol, or parenterally, including, for example,intramuscularly, subcutaneously, intraperitoneally, intraarterially,intravenously or intrathecally. Administration can be by means of a pumpfor periodic or continuous delivery. The compounds of the invention areadministered alone, or are combined with a pharmaceutically-acceptablecarrier or excipient according to standard pharmaceutical practice. Forthe oral mode of administration, the compounds of the invention are usedin the form of tablets, capsules, lozenges, chewing gum, troches,powders, syrups, elixirs, aqueous solutions and suspensions, and thelike. In the case of tablets, carriers that are used include lactose,sodium citrate and salts of phosphoric acid. Various disintegrants suchas starch, and lubricating agents such as magnesium stearate and talc,are commonly used in tablets. For oral administration in capsule form,useful diluents are lactose and high molecular weight polyethyleneglycols. If desired, certain sweetening and/or flavoring agents areadded. For parenteral administration, sterile solutions of the compoundsof the invention are usually prepared, and the pHs of the solutions aresuitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled to render the preparationisotonic. For ocular administration, ointments or droppable liquids maybe delivered by ocular delivery systems known to the art such asapplicators or eye droppers. Such compositions can include mucomimeticssuch as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid,EDTA or benzylchromium chloride, and the usual quantities of diluentsand/or carriers. For pulmonary administration, diluents and/or carrierswill be selected to be appropriate to allow the formation of an aerosol.

Suppository forms of the compounds of the invention are useful forvaginal, urethral and rectal administrations. Such suppositories willgenerally be constructed of a mixture of substances that is solid atroom temperature but melts at body temperature. The substances commonlyused to create such vehicles include theobroma oil, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weight and fatty acid esters of polyethyleneglycol. See, Remington's Pharmaceutical Sciences, 16th Ed., MackPublishing, Easton, Pa., 1980, pp. 1530-1533 for further discussion ofsuppository dosage forms. Analogous gels or creams can be used forvaginal, urethral and rectal administrations.

Numerous administration vehicles will be apparent to those of ordinaryskill in the art, including without limitation slow releaseformulations, liposomal formulations and polymeric matrices.

Examples of pharmaceutically acceptable acid addition salts for use inthe present invention include those derived from mineral acids, such ashydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids, and organic acids, such as tartaric, acetic, citric,malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic,p-toluenesulphonic and arylsulphonic acids, for example. Examples ofpharmaceutically acceptable base addition salts for use in the presentinvention include those derived from non-toxic metals such as sodium orpotassium, ammonium salts and organoamino salts such as triethylaminesalts. Numerous appropriate such salts will be known to those ofordinary skill.

The physician or other health care professional can select theappropriate dose and treatment regimen based on the subject's weight,age, and physical condition. Dosages will generally be selected tomaintain a serum level of compounds of the invention between about 0.01μg/cc and about 1000 μg/cc, preferably between about 0.1 μg/cc and about100 μg/cc. For parenteral administration, an alternative measure ofpreferred amount is from about 0.001 mg/kg to about 10 mg/kg(alternatively, from about 0.01 mg/kg to about 10 mg/kg), morepreferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kgto about 1 mg/kg), will be administered. For oral administrations, analternative measure of preferred administration amount is from about0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg),more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1mg/kg to about 1 mg/kg). For administrations in suppository form, analternative measure of preferred administration amount is from about 0.1mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1mg/kg.

For use in assaying for activity in inhibiting glycine transport,eukaryokic cells, preferably QT-6 cells derived from quail fibroblasts,have been transfected to express one of the three known variants ofhuman GlyT-1, namely GlyT-1a, GlyT-1b or GlyT-1c, or human GlyT-2. Thesequences of these GlyT-1 transporters are described in Kim et al.,Molec. Pharm. 45: 608-617, 1994, excepting that the sequence encodingthe extreme N-terminal of GlyT-1a was merely inferred from thecorresponding rat-derived sequence. This N-terminal protein-encodingsequence has now been confirmed to correspond to that inferred by Kim etal. The sequence of the human GlyT-2 is described by Albert et al., U.S.application Ser. No. 08/700,013, filed Aug. 20, 1996, which isincorporated herein by reference in its entirety. Suitable expressionvectors include pRc/CMV (Invitrogen), Zap Express Vector (StratageneCloning Systems, LaJolla, Calif.; hereinafter “Stratagene”), pBk/CMV orpBk-RSV vectors (Stratagene), Bluescript II SK+/− Phagemid Vectors(Stratagene), LacSwitch (Stratagene), pMAM and pMAM neo (Clontech),among others. A suitable expression vector is capable of fosteringexpression of the included GlyT DNA in a suitable host cell, preferablya non-mammalian host cell, which can be eukaryotic, fungal, orprokaryotic. Such preferred host cells include amphibian, avian, fungal,insect, and reptilian cells.

EXAMPLES Example 11-Methoxycarbonyl-2-phenyl-4-trimethylsilyl-1-buten-4-yne (C)

To a solution of palladium acetate (28 mg, 0.125 mmol) in anhydroustoluene (5 mL) was added tris(2,6-dimethoxyphenyl)phosphine (55 mg,0.125 mmol). After 15 minutes a solution of methyl phenylpropiolate(1.00 g, 6.24 mmol) in anhydrous toluene (5 mL) was added. After anadditional 5 minutes trimethylsilylacetylene (0.88 mL, 0.61 g, 6.24mmol) was added. After 16 hours the reaction mixture was concentrated.Column chromatography (10% ethyl acetate/hexanes) provided enyne C (1.39g, 86%) as a yellow oil. C: ¹H NMR (CDCl3, 300 MHz) 0.21 (s, 9H), 3.62(s, 3H), 6.34 (s, 1H), 7.33-7.44 (m, 5H).

Example 2 1-Hydroxy-3-phenyl-5-trimethylsilyl-2-penten-4-yne

A solution of the ester C (1.30 g, 5.03 mmol) in anhydrous toluene (20mL) was chilled in a dry ice/acetone bath. A 1.0 M solution ofdiisobutylaluminum hydride in toluene (12.6 mL, 12.6 mmol) was added.After 5 minutes the chilling bath was removed. After a further 15minutes the reaction mixture was re-chilled in an ice bath. The reactionwas quenched with the addition of celite and sodium sulphatedecahydrate. The slurry was diluted with ethyl acetate and filteredthrough celite. The filter cake was washed 3 times with ethyl acetate.The filtrate was washed with water and brine, dried (sodium sulphate),filtered, and concentrated to provide the intermediate alcohol (0.821 g,71%) as a yellow oil.: ¹H NMR (CDCl3, 300 MHz) 0.20 (s, 9H), 1.40 (t,1H), 4.31 (dd, 2H), 6.37 (t, 1H), 7.33-7.37 (m, 5H).

Example 3 1-Bromo-3-phenyl-5-trimethylsilyl-2-penten-4-yne (D)

A solution of the above alcohol (0.82 g, 3.56 mmol) in anhydrousdichloromethane (20 mL) was chilled in a dry ice/acetonitrile bath.Triphenylphosphine (1.40 g, 5.34 mmol) and N-bromosuccinimide (0.95 g,5.34 mmol) were added. After 30 minutes the reaction was quenched withsaturated sodium bicarbonate. The reaction mixture was partitionedbetween saturated sodium bicarbonate and dichloromethane. The organicphase was washed with brine, dried (sodium sulphate), filtered, andconcentrated to provide crude allylic bromide D, used directly in thenext step.

Example 4 N-(3-Phenyl-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

To a solution of the above bromide in anhydrous acetonitrile (15 mL) wasadded t-butyl sarcosine hydrochloride (0.71 g, 3.90 mmol), potassiumcarbonate (4.91 g, 35.5 mmol), and potassium iodide (2.95 g, 17.8 mmol).After 16 hours the reaction mixture was filtered through celite. Thefilter cake was washed with ethyl acetate. The filtrate was poured intowater and extracted with ethyl acetate. The organic phase was washedwith water and brine, dried (sodium sulphate), filtered, andconcentrated. Column chromatography (25% ethyl acetate/hexanes) providedproduct E (0.74 g, 58% over 2 steps) as a pale yellow oil. E: ¹H NMR(CDCl₃, 300 MHz) 0.19 (s, 9H), 1.41 (s, 9H), 2.32 (s, 3H), 3.10 (s, 2H),3.31 (d, 2H), 6.33 (t, 1H), 7.26-7.38 (m, 5H).

Example 5 N-(3-Phenyl-2-penten-4-yn-1-yl)-sarcosine, ^(t)butyl ester (F)

To a solution of the above compound (0.74 g, 2.06 mmol) in methanol (10mL) was added potassium carbonate (1.42 g, 10.3 mmol). After 20 minutesthe reaction mixture was poured into water and extracted 2 times withethyl acetate. The combined organic extracts were washed with brine,dried (sodium sulphate), filtered, and concentrated to provide terminalacetylene F (0.58 g, 99%) as an off-white solid. F: ¹H NMR (CDCl₃, 300MHz) 1.41 (s, 9H), 2.33 (s, 3H), 2.96 (s, 1H), 3.10 (s, 2H), 3.33 (d,2H), 6.37 (t, 1H), 7.26-7.39 (m, 5H).

Example 6-1N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, ^(t)butylester, (G)

To a solution of the terminal acetylene F (50 mg, 0.175 mmol) intriethylamine (2 mL) was added 4-fluoroiodobenzene (26 μL, 51 mg, 0.228mmol), tetrakis(triphenylphosphine)palladium(O) (20 mg, 0.0175 mmol),and copper(I) iodide (10 mg, 0.0525 mmol). After 16 hours the reactionmixture was diluted with dichloromethane and filtered. The filtrate wasconcentrated. Column chromatography (25% ethyl acetate/hexanes) providedacetylene G (51 mg, 77%) as a yellow oil. G: ¹H NMR (CDCl₃, 300 MHz)1.42 (s, 9H), 2.35 (s, 3H), 3.13 (s, 2H), 3.36 (d, 2H), 6.37 (t, 1H),7.00 (dd, 2H), 7.26-7.44 (m, 7H).

In a similar fashion the following compounds were prepared fromintermediate F and 1.3 equivalents of the corresponding aryliodidetreated under the conditions described above.:

6-2: N-(5-(2-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 2-fluoroiodobenzene to provide 45 mg(68%) of a yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.42 (s, 9H), 2.36 (s,3H), 3.14 (s, 2H), 3.39 (d, 2H), 6.43 (t, 1H), 7.06 (dd, 2H), 7.24-7.44(m, 7H).

6-3: N-(5-(2,4-Difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 2,4-difluoroiodobenzene to provide 49mg (70%) of a yellow oil. ¹HNMR (CDCl₃, 300 MHz) 1.42 (s, 9H), 2.36 (s,3H), 3.13 (s, 2H), 3.38 (d, 2H), 6.42 (t, 1H), 6.83 (dd, 2H), 7.26-7.44(m, 6H).

6-4: N-(5-(3-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3-nitroiodobenzene to provide 73 mg(102%) of a yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.42 (s, 9H), 2.36 (s,3H), 3.13 (s, 2H), 3.38 (d, 2H), 6.45 (t, 1H), 7.26-7.40 (m, 5H), 7.48(dd, 1H), 7.72 (d, 1H), 8.13 (d, 1H), 8.27 (s, 1H).

6-5: N-(5-(4-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-nitroiodobenzene to provide 31 mg(44%) of a yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.42 (s, 9H), 2.36 (s,3H), 3.14 (s, 2H), 3.38 (d, 2H), 6.47 (t, 1H), 7.34-7.43 (m, 5H), 7.57(d, 2H), 8.17 (d, 2H).

6-6: N-(3-Phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 2-thiomethyliodobenzene to provide 19mg (26%) of a yellow oil. ¹H NMR (CDCl₃) 1.42 (s, 9H), 2.36 (s, 3H),2.46 (s, 3H), 3.14 (s, 2H), 3.39 (d, 2H), 6.45 (t, 1H), 7.06 (dd, 1H),7.14 (d, 1H), 7.24-7.40 (m, 6H), 7.46 (d, 1H).

6-7: N-(5-(4-Chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-chloroiodobenzene to provide 52 mg(75%) of a yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.42 (s, 9H), 2.35 (s,3H), 3.13 (s, 2H), 3.36 (d, 2H), 6.38 (t, 1H), 7.26-7.39 (m, 9H).

6-8: N-(5-(4-Isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-isopropyliodobenzene to provide 38mg (53%) of a yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.23 (d, 6H), 1.42 (s,9H), 2.36 (s, 3H), 2.89 (hept, 1H), 3.13 (s, 2H), 3.36 (d, 2H), 6.36 (t,1H), 7.16 (d, 2H), 7.26-7.42 (m, 7H).

6-9:N-(5-(3,5-Bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3,5-Bis(trifluoromethyl)iodobenzeneto provide 40 mg (46%) of a yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.42 (s,9H), 2.36 (s, 3H), 3.14 (s, 2H), 3.38 (d, 2H), 6.47 (t, 1H), 7.26-7.44(m, 5H), 7.77 (s, 1H), 7.86 (s, 2H).

6-10: N-(3,5-Diphenyl-2-penten-4-yn-1-yl)-sarcosine, ^(t)butyl ester,(G)

Prepared in a similar fashion from iodobenzene to provide 46 mg (33%) ofa yellow oil. ¹H NMR (CDCl₃, 300 MHz) 1.42 (s, 9H), 2.36 (s, 3H), 3.13(s, 2H), 3.36 (d, 2H), 6.38 (t, 1H), 7.26-7.46 (m, 10H).

6-11: N-(3-Phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-thiomethyliodobenzene to provide30.0 mg (70%) of a yellow oil.

6-12: N-(3-Phenyl-5-(4-methylphenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-methyliodobenzene to provide 33.0mg (85%) of a yellow oil.

6-13: N-(5-(3-Thiophene)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3-iodothiophene to provide 30.0 mg(78%) of a brown oil.

6-14: N-(3-Phenyl-5-(4-tbutylphenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-t-butyliodobenzene to provide 38.0mg (86%) of a yellow oil.

6-15: N-(5-(4-Methoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-methoxyiodobenzene to provide 31.0mg (73%) of a yellow oil.

6-16: N-(5-(2-Isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 2-isopropyliodobenzene to provide27.0 mg (64%) of an amber oil.

6-17: N-(5-(4-diphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-biphenyliodobenzene to provide 260mg (85%) of a yellow oil.

6-18:N-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-trifluoromethyliodobenzene toprovide 240 mg 80%) of a yellow oil.

6-19: N-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-benzyliodobenzene to provide 240 mg(80%) of a light yellow oil.

6-20: N-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-ethyliodobenzene to provide 240 mg(88%) of product. 6-20: ¹H NMR (CDCl₃, 300 MHz) 1.22 (t, 3H), 1.43 (s,9H), 2.36 (s, 3H), 2.63(q, 2H), 3.13 (s, 2H), 3.36 (d, 2H), 6.37 (t,1H), 7.13 (d, 2H), 7.26-7.43 (m, 7H).

6-21: N-(5-(4-npropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-n-propyliodobenzene to provide 240mg (85%) of product. 6-21: ¹H NMR (CDCl₃, 300 MHz) 0.93 (t, 3H),1.43 (s,9H), 1.57 (sextet, 2H), 2.36 (s, 3H), 2.57 (t, 2H), 3.14 (s, 2H), 3.37(d, 2H), 6.37 (t, 1H), 7.12 (d, 2H), 7.25-7.43 (m, 7H).

6-22: N-(5-(4-nbutylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-n-butyliodobenzene to provide 260mg (89%) of a yellow oil.

6-23: N-(5-(4-npentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-n-pentyliodobenzene to provide 240mg (79%) of a yellow oil.

6-24: N-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-phenoxyiodobenzene to provide 34.7mg (56%) of a yellow film.

6-25: N-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 1-iodonaphthalene to provide 35.8 mg(63.5%) of product. 6-25: ¹H NMR (CDCl₃, 300 MHz) 1.43 (s, 9H), 2.40 (s,3H), 3.17 (s, 2H), 3.42 d, 2H), 6.53 (t, 1H), 7.33-7.57 (m, 8H), 7.67(d, 1H), 7.75-7.85 (m, 2H), 8.30 (d, 1H).

6-26: N-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-methyliodobenzene to provide 34.7mg (88%) of a light yellow oil.

6-27: N-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3-isopropyliodobenzene to provide17.6 mg (42%) of product. 6-27: ¹H NMR (CDCl₃, 300 MHz) 1.23 (d,6H),1.42 (s, 9H), 2.36 (s, 3H), 2.87 (septtet, 1H), 3.13 (s, 2H), 3.36(d, 2H), 6.38 (t, 1H), 7.15-7.42 (m, 8H), 7.70-7.71 (m, 1H).

6-28: N-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 2-iodonaphthalene to provide 30.0 mg(69%) of a colourless oil.

6-29: N-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3,4-dimethyliodobenzene to provide40.0 mg (98%) of a yellow film.

6-30: N-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 2-isopropyliodobenzene to provide27.0 mg (64%) of an amber oil.

6-31:N-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3,4-methylenedioxyiodobenzene toprovide 40.0 mg (94%) of a yellow oil.

6-32: N-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-pyrrolyliodobenzene to provide 41.0mg (92%) of a light yellow oil.

6-33:N-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 4-trifluoromethoxyiodobenzene toprovide 28.5 mg (61%) of product. 6-33: ¹H NMR (CDCl3, 300 MHz) 1.42 (s,9H), 2.35 (s, 3H), 3.13 (s, 2H), 3.36 (d, 2H), 6.39 (t, 1H), 7.15 (d,2H), 7.26-7.39 (d, 2H), 7.46 (d, 2H).

6-34: N-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepared in a similar fashion from 3,4-dimethoxyiodoenzene to provide35.0 mg (80%) of a colourless oil.

In a similar fashion the following compounds are prepared fromintermediate F and 1.3 equivalents of the corresponding aryliodidetreated under the conditions described above:

6-35: N-(5-(2-quinoline)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester, (G)

Prepare in a similar fashion from 2-iodoquinolene.

6-36: N-(5-(indanyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, ^(t)butylester, (G)

Prepare in a similar fashion from iodoindane.

Example 7-1N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

A solution of t-butyl ester 6-1 (51 mg, 0.135 mmol) in 96% formic acidwas heated at 40 C. for 16 hours. The reaction mixture was cooled andconcentrated. The residue was taken up into dichloromethane and passedthrough a 2 g solid phase extraction tube, eluting with dichloromethane,then ethyl acetate, then methanol. The methanol fraction wasconcentrated to provide amino acid 7-1 (39 mg, 90%) as a colourlessfoam: ¹H NMR (CDCl₃, 300 MHz) 2.72 (s, 3H), 3.49 (s, 2H), 3.92 (d, 2H),6.38 (t, 1H), 6.98 (dd, 2H), 7.26-7.42 (m, 7H). HRMS calc 324.1400,found 324.1386.

In a similar fashion the following compounds were prepared from thecorresponding intermediate treated under the conditions described above:

7-2: N-(5-(2-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-2 to provide 31 mg(81%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.68 (s, 3H), 3.47(s, 2H), 3.90 (s, 2H), 6.43 (s, 1H), 7.05 (dd, 2H), 7.23-7.42 (m, 7H).HRMS calc 324.1400, found 324.1408.

7-3: N-(5-(2,4-Difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-3 to provide 34 mg(82%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.70 (s, 3H), 3.48(s, 2H), 3.91 (s, 2H), 6.42 (s, 1H), 6.78 (dd, 2H), 7.26-7.38 (m, 6H).HRMS calc 342.1306, found 342.1333.

7-4: N-(5-(3-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-4 to provide 42 mg(68%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.72 (s, 3H), 3.50(s, 2H), 3.94 (d, 2H), 6.50 (t, 1H), 7.26-7.48 (m, 6H), 7.70 (d, 1H),8.12 (d, 1H), 8.22 (s, 1H). HRMS calc 351.1345, found 351.1353.

7-5: N-(5-(4-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-5 to provide 21 mg(80%) of a colourless foam. ¹H NMR (CDCl3, 300 MHz) 2.66 (s, 3H), 3.43(s, 2H), 3.85 (d, 2H), 6.51 (s, 1H), 7.26-7.53 (m, 5H), 7.54 (d, 2H),8.14 (d, 2H).

7-6: N-(3-Phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-6 to provide 14 mg(87%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.42 (s, 3H), 2.66(s, 3H), 3.48 (s, 2H), 3.88 (s, 2H), 6.40 (s, 1H), 7.12-7.68 (m, 9H).

7-7: N-(5-(4-Chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-7 to provide 40 mg(90%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.68 (s, 3H), 3.48(s, 2H), 3.87 (s, 2H), 6.39 (s, 1H), 7.24-7.37 (m, 9H). HRMS calc340.1104, found 340.1097.

7-8: N-(5-(4-Isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-8 to provide 32 mg(99%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 1.21 (d, 6H), 2.65(s, 3H), 2.86 (hept, 1H), 3.43 (s, 2H), 3.86 (d, 2H), 6.36 (t, 1H), 7.14(d, 2H), 7.26-7.36 (m, 7H). HRMS calc 348.1964, found 348.1998.

7-9:N-(5-(3,5-Bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-9 to provide 26 mg(76%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.67 (s, 3H), 3.46(s, 2H), 3.87 (d, 2H), 6.52 (t, 1H), 7.26-7.40 (m, 5H), 7.77 (s, 1H),7.83 (s, 2H). HRMS calc 442.1242, found 442.1173.

7-10: N-(3,5-Diphenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-10 to provide 18 mg(46%) of a colourless foam. ¹H NMR (CDCl₃, 300 MHz) 2.69 (s, 3H), 3.48(s, 2H), 3.89 (d, 2H), 6.40 (t, 1H), 7.26-7.44 (m, 10H). HRMS calc306.1494, found 306.1432.

7-11: N-(5-(4-diphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-17 to provide 220.0 mg(97%) of a yellow solid.

7-12:N-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-18 to provide 200.0 mg(96%) of a yellow film.

7-13: N-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-19 to provide 190.0 mg(87%) of a light yellow solid.

7-14: N-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-20, to provide 176.1mg (86%) of a green-grey solid.

7-15: N-(5-(4-^(n)propylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-21 to provide 190.9 mg(93%) of an orange-white solid.

7-16: N-(5-(4-^(n)butylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-22 to provide 206.0 mg(91%) of a yellow solid.

7-17: N-(5-(4-^(n)pentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-23 to provide 204.4 mg(98%) of a yellow solid.

7-18: N-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-24 to provide 33.0 mg(100%) of a light yellow solid.

7-19: N-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-25 to provide 25.4 mg(82%) of a yellow oil.

7-20: N-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-26 to provide 12.6 mg(55%) of a yellow solid.

7-21: N-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-27 to provide 12.6 mg(83%) of a green-brown oil.

7-22: N-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-28 to provide 25.1 mg(97%) of a yellow solid.

7-23: N-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-29 to provide 33.2 mg(97%) of a light yellow solid.

7-24: N-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-30 to provide 15.2 mg(66%) of a flaky yellow solid.

7-25:N-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-31 to provide 9.5 mg(31%) of an off-white solid.

7-26: N-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-32 to provide 24.1 mg(68%) of a yellow solid.

7-27:N-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-33 to provide 23.0 mg(92%) of a yellow solid.

7-28: N-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H)

Prepared in a similar fashion from intermediate 6-34 to provide 25.7 mg(86%) of a yellow solid.

In a similar fashion the following compounds are prepared from thecorresponding intermediate treated under the conditions described above:

7-29: N-(5-(2-quinoline)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Prepare in a similar fashion from 6-35.

7-30: N-(5-(indanyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Prepare in a similar fashion from 6-36.

Example 8-1N-(3-Phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine, (H)

A solution of ^(t)butyl ester 6-11 G(vi) (30.0 mg, 0.0736 mmol) in 96%formic acid was heated at 50 C. for 3 hours. The reaction mixture wascooled and concentrated. The residue was taken up in dichloromethane andpassed through a 2 g solid phase extraction tube, eluting withdichloromethane, then ethyl acetate, then methanol. The methanolfraction was concentrated to provide amino acid 8-1 (14.9 mg, 58%) as alight yellow solid.

In a similar fashion the following compounds were prepared from thecorresponding intermediate under the conditions described above:

8-2: N-(5-(4-Methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-12 to provide 30.0 mg(91%) of a light yellow solid.

8-3: N-(3-Phenyl-5-(3-thiophene)-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-13 to provide 22.0 mg(87%) of a brown solid foam.

8-4: N-(3-Phenyl-5-(4-tbutylphenyl)-2-penten-4-yn-1-yl)-sarcosine, (H)

Prepared in a similar fashion from intermediate 6-14 to provide 22.9 mg(66%) of a light yellow solid.

Example 9 N-(5-(4-Bromophenyl)-3-phenyl-2-penten-4yn-1-yl)sarcosine^(t)butyl ester, (S)

To a solution of terminal acetylene F (3.25 g, 11.4 mmol) in Et3N (75mL) was added 4-bromoiodobenzene (4.19 g, 14.8 mmol), Pd(PPh₃)₄ (1.32 g,1.14 mmol), and CuI (0.65 g, 3.42 mmol). The mixture was stirredovernight, and concentrated. Column chromatography (10% EtOAc/hexanes)provided bromide S (3.84 g, 76%) as a yellow oil.

Example 10-1N-(5-(4-(3furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine ^(t)Butylester, (G′)

To a solution of bromide S (3.84 g, 8.72 mmol) in DME (25 mL) was added3furanboronic acid (1.47 g, 13.1 mmol), Pd(PPh₃)₄ (1.01 g, 0.872 mmol),and 2M Na₂CO₃ (25 mL). The mixture was refluxed for 1 hour, cooled, andpartitioned between EtOAc and water. The organic phase was washed withbrine, dried (MgSO₄), filtered, and concentrated. Column chromatography(10-12.5% EtOAc/hexanes) provided ester G′ (2.62 g, 78%) as a yellowoil.

In a similar fashion the following compounds were made from thecorresponding boronic acid under the conditions described above:

10-2:N-(5-(4-(3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine^(t)Butyl ester, (G′)

Prepared in a similar fashion from 3-thiopheneboronic acid to provide21.0 mg (46%) of a colourless film.

In a similar fashion the following compounds are made from thecorresponding boronic acid under the conditions described above:

10-3:N-(5-(4-(4Methyl-3-thiophene)phenyl)-3-phenyl-2-penten-4yn-1-yl)-sarcosinet-Butyl ester

Prepare in a similar fashion from S and 4-methyl-3-thiopheneboronicacid.

10-4:N-(5-(4-(4Methyl-3-furyl)phenyl)-3-phenyl-2-penten-4yn-1-yl)-sarcosinet-Butyl ester

Prepare in a similar fashion from S and 4-methyl-3-furanboronic acid.

10-5:N-(5-(4-(cyclohexyl)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosinetButyl Ester

Prepare in a similar fashion from S and cyclohexylboronic acid.

10-6:N-(5-(4-(cyclopentyl)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosinetButyl Ester

Prepare in a similar fashion from S and cyclopentylboronic acid.

Example 11-1N-(5-(4-(3furyl)phenyl)-3-phenyl-2-penten-4yn-1-yl)-sarcosine, (H′)

The ester G′ (2.62 g, 6.13 mmol) was dissolved in 96% formic acid (26mL). The solution was warmed at 40° C. overnight, then concentrated.Column chromatography (0-8% MeOH/CH₂Cl₂) provided a pale yellow solid.Trituration with MeOH provided pure H′ (0.78 g, 34%) as a white solid.Conversion of 11-1 to the corresponding sodium salt was achieved bysuspending 11-1 in methanol and adding 1 equivalent of 6M sodiumhydroxide. The solution was then concentrated and the residue wastriturated with isopropanol to provide a white solid.

In a similar fashion the following compounds were made from thecorresponding intermediate treated under the conditions described above:

11-2:N-(5-(4-(3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,(H′)

Prepared in a similar fashion from intermediate 10-2 to provide 11.7 mg(59%) of an off-white solid.

11-3:N-(5-(4-(4-Methyl-3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Prepare in a similar fashion from 10-3.

11-4:N-(5-(4-(4-Methyl-3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Prepare in a similar fashion from 10-4.

11-5:N-(5-(4-(cyclohexyl)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Prepare in a similar fashion from 10-5.

10-6:N-(5-(4-(cyclopentyl)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Prepare in a similar fashion from 10-6.

Example 12-1 Ethyl 4-(trifluoromethyl)phenylpropiolate (A)

To a solution of 4-iodobenzotrifluoride (256 mg, 0.941 mmol) intriethylamine (2.5 mL) was added ethyl propiolate (0.124 mL, 120 mg,1.22 mmol), Pd(PPh₃)₄ (109 mg, 0.0941 mmol), and CuI (54 mg, 0.282mmol). After 24 hours the reaction mixture was concentrated. Columnchromatography (10% EtOAc/hexanes) provided 12-1(149 mg, 65%) as acolourless oil.

In a similar fashion the following compounds were prepared from thecorresponding aryliodide and 1.3 equivalents of ethylpropiolate treatedunder the conditions described above:

12-2: Ethyl 4-fluorophenylpropiolate (A)

Prepared in a similar fashion from 4-fluoroiodobenzene to provide 33 mg(4%) of a colourless solid.

12-3: Ethyl 2-fluorophenylpropiolate (A)

Prepared in a similar fashion from 2-fluoroiodobenzene to provide 3.46 g(93%) of a colourless oil.

12-4: Ethyl 4-chlorophenylpropiolate (A)

Prepared in a similar fashion from 4-chloroiodobenzene to provide 4.60 g(100%) of a colourless solid.

12-5: Ethyl 2-chlorophenylpropiolate (A)

Prepared in a similar fashion from 2-chloroiodobenzene to provide 7.64 g(100%) of a yellow liquid.

12-6: Ethyl 3-thienylpropiolate (A)

Prepared in a similar fashion from 3-thienyliodobenzene to provide 90 mg(53%/o) of a yellow solid.

12-7: Ethyl 4-methoxyphenylpropiolate (A)

Prepared in a similar fashion from 4-methoxyiodobenzene to provide 117mg (13%) of a colourless oil.

Example 13-11-Ethoxycarbonyl-2-(4-(trifluoromethyl)phenyl)-4-trimethylsilyl-1-buten-4-yne(C)

To a solution of Pd(OAc)2 (2.6 mg, 0.0115 mmol) in PhMe (2 mL) was addedtris(2,6-dimethoxyphenyl)phosphine (5.1 mg, 0.0115 mmol). After 15minutes a solution of 12-1 (117 mg, 0.573 mmol) in PhMe (3 mL) wasadded. After 5 minutes (trimethylsilyl)acetylene (0.081 mL, 56 mg, 0.573mmol) was added. After 21 hours the reaction mixture was concentrated.Column chromatography (10% EtOAc/hexanes) provided 13-1 (144 mg, 83%) asa yellow oil.

In a similar fashion the following compounds were prepared from thecorresponding propiolate intermediate treated by the conditionsdescribed above:

13-2: 1-Ethoxycarbonyl-2-(4-fluorophenyl)-4-trimethylsilyl-1-buten-4-yne(C)

Prepared in a similar fashion from intermediate 12-2 to provide 29 mg(58%) of a yellow oil.

13-3: 1-Ethoxycarbonyl-2-(2-fluorophenyl)-4-trimethylsilyl-1-buten-4-yne(C)

Prepared in a similar fashion from intermediate 12-3 to provide 4.19 g(80%) of a yellow oil.

13-4: 1-Ethoxycarbonyl-2-(4-chlorophenyl)-4-trimethylsilyl-1-buten-4-yne(C)

Prepared in a similar fashion from intermediate 12-4 to provide 4.04 g(60%) of a brown oil.

13-5: 1-Ethoxycarbonyl-2-(2-chlorophenyl)-4-trimethylsilyl-1-buten-4-yne(C)

Prepared in a similar fashion from intermediate 12-5 to provide 10.4 g(93%) of a brown oil.

13-6: 1-Ethoxycarbonyl-2-(3-fluorophenyl)-4-trimethylsilyl-1-buten-4-yne(C)

Prepared in a similar fashion from the commercially availableintermediate Ethyl 3-fluorophenylpropiolate to provide 0.73 g (85%) of ayellow oil.

13-7: 1-Ethoxycarbonyl-2-(3-thienyl)-4-trimethylsilyl-1-buten-4-yne (C)

Prepared in a similar fashion from intermediate 12-6 to provide 123 mg(90%) of a yellow oil.

13-8:1-Ethoxycarbonyl-2-(4-methoxyphenyl)-4-trimethylsilyl-1-buten-4-yne (C)

Prepared in a similar fashion from intermediate 12-7 to provide 144 mg(83%) of a yellow oil.

Example 14-11-Hydroxy-3-(4-(trifluoromethyl)phenyl)-5-trimethylsilyl-2-penten-4-yne

A solution of 13-1 (144 mg, 0.476 mmol) in anhydrous PhMe (2 mL) waschilled in a dry-ice/acetone bath. A 1.0 M solution of DIBAL-H in PhMe(1.2 mL, 1.19 mmol) was added dropwise. After 5 minutes the chillingbath was removed. After an additional 15 minutes the reaction mixturewas chilled in an ice bath and Celite and Na₂SO410H₂O were added toquench the reaction. The reaction mixture was filtered through Celite.The filtrate was concentrated. Column chromatography (20% EtOAc/hexanes)provided 14-1 (114 mg, 92%) as a yellow oil.

In a similar fashion the following compounds were prepared form thecorresponding ester intermediates under the conditions described above:

14-2: 1-Hydroxy-3-(4-fluorophenyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-2 to provide 19 mg(80%) of a colourless oil.

14-3: 1-Hydroxy-3-(2-fluorophenyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-3 to provide 2.65 g(74%) of a yellow oil.

14-4: 1-Hydroxy-3-(4-chlorophenyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-4 to provide 2.16 g(62%) of a yellow oil.

14-5: 1-Hydroxy-3-(2-chlorophenyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-5 to provide 4.86 g(54%) of a yellow oil.

14-6: 1-Hydroxy-3-(3-fluorophenyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-6 to provide 0.47 g(74%) of a pale yellow oil.

14-7: 1-Hydroxy-3-(3-thienyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-7 to provide 56 mg(77%) of a yellow oil.

14-8: 1-Hydroxy-3-(4-methoxyphenyl)-5-trimethylsilyl-2-penten-4-yne

Prepared in a similar fashion from intermediate 13-8 to provide 114 mg(92%) of a yellow oil.

Example 15-1N-(3-(4-(Trifluoromethyl)phenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

A solution of 14-1 (115 mg, 0.385 mmol) in anhydrous CH₂Cl₂ (4 mL) waschilled in a dry-ice/acetonitrile bath. PPh₃ (152 mg, 0.578 mmol) andNBS (103 mg, 0.578 mmol) were added. After 40 minutes saturated NaHCO₃was added. The reaction mixture was partitioned between CH₂Cl₂ andsaturated NaHCO₃. The organic phase was washed with brine, dried(Na₂SO₄), filtered, and concentrated to provide crude intermediate D(1-Bromo-3-(4-(trifluoromethyl)phenyl)-5-trimethylsilyl-2-penten-4-yne)used directly in the next step.

To a solution of the crude bromide D (139 mg, 0.385 mmol) in anhydrousMeCN (4 mL) was added t-butyl sarcosine hydrochloride (77 mg, 0.424mmol), K₂CO₃ (532 mg, 3.85 mmol), and KI (320 mg, 1.92 mmol). After 24hours the reaction mixture was poured into water and extracted withEtOAc. The organic phase was washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. Column chromatography (15%EtOAc/hexanes) provided 15-1 (62 mg, 38% over 2 steps) as a colourlessoil.

In a similar fashion the following compounds were prepared from thecorresponding crude bromide treated under the conditions describedabove:

15-2:N-(3-(4-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-2 to provide 18 mg(63% over 2 steps) of a colourless oil.

15-3:N-(3-(2-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-3 to provide 3.24 g(81% over 2 steps) of a yellow oil.

15-4:N-(3-(4-chlorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-4 to provide 1.55 g(49%) of a yellow oil.

15-5:N-(3-(2-chlorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-5 to provide 5.39 g(75%) of a pale yellow oil.

15-6:N-(3-(3-fluorophenyl)-5-(trimethylsilyi)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-6 to provide 0.63 g(89%) of a yellow oil.

15-7: N-(3-(3-thienyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-7 to provide 61 mg(71%) of a yellow oil.

15-8:N-(3-(4-methoxyphenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (E)

Prepared in a similar fashion from intermediate 14-8 to provide 14 mg(10%) of a yellow oil.

Example 16-1N-(3-(4-(Trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

To a solution of 15-1 (62 mg, 0.146 mmol) in MeOH (2 mL) was added K₂CO₃(101 mg, 0.730 mmol). After 15 minutes the reaction mixture was pouredinto water and extracted with EtOAc. The organic phase was washed withbrine, dried (MgSO₄), filtered, and concentrated to provide 16-1 (36 mg,71%) as a yellow oil.

In a similar fashion the following compounds were prepared from thecorresponding trimethylsilyl intermediates under the conditionsdescribed above:

16-2: N-(3-(4-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

Prepared in a similar fashion from intermediate 15-2 to provide 13 mg(93%) of a yellow oil.

16-3: N-(3-(2-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

Prepared in a similar fashion from intermediate 15-3 to provide 2.22 g(85%) of a colourless oil.

16-4: N-(3-(4-chlorophenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

Prepared in a similar fashion from intermediate 15-4 to provide 0.80 g(76%) of a yellow oil.

16-5: N-(3-(2-chlorophenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

Prepared in a similar fashion from intermediate 15-5 to provide 3.72 g(85%) of a yellow oil.

16-6: N-(3-(3-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

Prepared in a similar fashion from intermediate 15-6 to provide 0.42 g(83%) of a pale yellow solid.

16-7: N-(3-(3-thienyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butyl ester (F)

Prepared in a similar fashion from intermediate 15-7 to provide 46 mg(96%) of a yellow solid.

16-8: N-(3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)sarcosine, ^(t)butylester (F)

Prepared in a similar fashion from intermediate 15-8 to provide 15 mg (I36%) of a yellow oil.

Example 17-1N-(5-(4-Isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine,butyl ester (G)

To a solution of 16-1 (35 mg, 0.099 mmol) in triethylamine (2 mL) wasadded 4-iodoisopropylbenzene (32 mg, 0.129 mmol), Pd(PPh₃)₄ (11 mg,0.0099 mmol), and CuI (5.5 mg, 0.029 mmol). After 18 hours the reactionmixture was concentrated. Column chromatography (10% EtOAc/hexanes)provided 17-1 (40 mg, 86%) as a colourless oil.

In a similar fashion the following compounds were prepared from 1.3equivalents of the appropriate aryliodide with the corresponding alkyneintermediate according to the conditions described above:

17-2:N-(5-(4-Isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-2 and4-isopropyliodobenzene to provide 14 mg (76%) of a colourless oil.

17-3:N-(5-(4-Isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-3 and4-isopropyliodobenzene to provide 440 mg (79%) of a yellow oil.

17-4:N-(5-(4-t-Butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-3 and4-t-butyliodobenzene to provide 500 mg (87%) of a yellow oil.

17-5:N-(5-(4-Isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-4 and4-isopropyliodobenzene to provide 0.50 g (883) of a pale yellow oil.

17-6:N-(5-(4-t-Butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-4 and4-tbutyliodobenzene to provide 514 mg (83%) of a pale yellow oil.

17-7:N-(5-(4-Isoproylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-5 and4-isopropyliodobenzene to provide 0.53 g (97%) of a yellow oil.

17-9:N-(5-(4-t-Butylphenyl)-3-(2-clorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-5 and4-t-biutyliodobenzene to provide 0.52 g (92%) of a yellow oil.

17-9:N-(5-(4-Isopropylphenyl)-3-(3-flurophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-6 and4-isopropyliodobenzene to provide 0.16 g (03%) of a yellow oil.

17-10:N-(5-(4-Isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-7 and4-isopropyliodobenzene to provide 54 mg (86%) of a yellow oil.

17-11:N-(5-(4-Isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-8 and4-isopropyliodobenzene to provide 21 mg (129%) of a colourless oil.

17-12:N-(5-(3,4-Methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-6 and3,4-methylenedioxyiodobenzene to provide 74.1 mg (106%) of a brown oil.

17-13:N-(5-(4-Ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-5 and4-ethyliodobenzene to provide 44.0 mg (110%) of a light yellow oil.

17-4:N-(5-(4-Propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine,^(t)butyl ester (G)

Prepared in a similar fashion from intermediate 16-5 and4-propyliodobenzene to provide 39.5 mg (96%) of a light yellow oil.

Example 18-1N-(5-(4-Isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

A solution of 17-1 (40 mg, 0.0849 mmol) in formic acid (2 mL) was warmedat 40° C. for 18 hours. The reaction mixture was concentrated. Columnchromatography (0-100% MeOH/CH₂Cl₂) provided 18-1 (36 mg, 99%) as ayellow oil.

In a similar fashion the following compounds were prepared from thecorresponding t-butyl ester intermediate under the conditions describedabove:

18-2:N-(5-(4-Isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-2 to provide 13 mg(107%) of a colourless oil.

18-3:N-(5-(4-Isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-3 to provide 379 mg(99%) of a pale yellow oil.

18-4:N-(5-(4-t-Butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-4 to provide 434 mg(100%) of a yellow oil.

18-5:N-(5-(4-Isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sacosine(H)

Prepared in a similar fashion from intermediate 17-5 to provide 436 mg(96%) of a beige solid.

18-6:N-(5-(4-t-Butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-6 to provide 408 mg(88%) of a beige solid.

18-7:N-(5-(4-Isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-7 to provide 438 mg(95%) of an off-white foam.

18-8:N-(5-(4-t-Butylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-8 to provide 448 mg(97%) of a colourless foam.

18-9:N-(5-(4-Isopropylphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-9 to provide 0.12 g(93%) of a colourless oil.

18-10:N-(5-(4-Isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Prepared in a similar fashion from intermediate 17-10 to provide 34 mg(72%) of a yellow solid.

18-11:N-(5-(4-Isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-11 to provide 14 mg(76%) of a colourless oil.

18-12:N-(5-(3,4-Methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-12 to provide 64.1 mg(88%) of a orange-brown oil.

18-13:N-(5-(4-Ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-13 to provide 30.1 mg(79%) of a colourless oil.

18-14:N-(5-(4-Propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine(H)

Prepared in a similar fashion from intermediate 17-14 to provide 13.9 mg(40%) of a light yellow oil.

Example 20

Assay of Transport via GlyT-1

This example illustrates a method for the measurement of glycine uptakeby transfected cultured cells.

Cells stably transfected with GlyT-1 C (see Kim, et al., MolecularPharmacology, 45, 1994:608-617) were washed twice with HEPES bufferedsaline (HBS). The cells were then incubated 10 minutes at 37 C., afterwhich a solution was added containing 50 nM [³H]glycine (17.5 Ci/mmol)and either (a) no potential competitor, (b) 10 mM nonradioactive glycineor (c) a concentration of a candidate drug. A range of concentrations ofthe candidate drug was used to generate data for calculating theconcentration resulting in 50% of the effect (e.g., the IC₅₀s, which arethe concentrations of drug inhibiting glycine uptake by 50%). The cellswere then incubated another 10 minutes at 37° C., after which the cellswere aspirated and washed three times with ice-cold HBS. The cells wereharvested, scintillant was added to the cells, the cells were shaken for30 minutes, and the radioactivity in the cells was counted using ascintillation counter. Data were compared between the same cellscontacted or not contacted by a candidate agent, depending on the assaybeing conducted.

The compounds of the present invention were active as GlyT-1 inhibitors.

Example 21

Assay of Binding to NMDA Receptors

This example illustrates binding assays to measure interaction ofcompounds with the glycine site on the NMDA receptor. Direct binding of[³H]glycine to the NMDA-glycine site was performed according to themethod of Grimwood et al., Molecular Pharmacology, 41, 923-930 (1992);Yoneda et al., J. Neurochem, 62, 102-112 (1994).

The binding test was performed in eppendorf tubes containing 150 μg ofmembrane protein and 50 nM [³H]glycine in a volume of 0.5 ml.Non-specific binding was determined with 1 mM glycine. Drugs weredissolved in assay buffer (50 mM Tris-acetate, pH 7.4) or DMSO (finalconcentration of 0.1%). Membranes were incubated on ice for 30 minutesand bound radioligand was separated from free radioligand by filtrationon Whatman GF/B glass fiber filters or by centrifugation (18,000×g, 20min). Filters or pellet was washed three times quickly with ice-cold 5mM Tris-acetate buffer. Filters were dried and placed in scintillationtubes and counted. Pellets were dissolved in deoxycholate/NaOH (0.1 N)solution overnight, neutralized and radioactivity was determined byscintillation counting.

A second binding test for the NMDA-glycine site used[3H]dichlorokynurenic acid (DCKA) and membranes prepared as above. See,Yoneda et al., J. Neurochem., 60,634-645 (1993). The binding assay wasperformed as described for [³H]glycine above except that [³H]DCKA wasused to label the glycine site. The final concentration of [³H]DCKA was10 nM, and the assay was performed for 10 minutes on ice.

A third binding test used for the NMDA-glycine site used indirectassessment of affinity of ligands for the site by measuring the bindingof [3H]MK-801 (dizocilpine). See, Palmer and Burns, J. Neurochem., 62,187-196 (1994). Preparation of membranes for the test was the same asabove. The binding assay allowed separate detection of antagonists andagonists.

The third binding test was operated to identify antagonists as follows:100 μg of membranes were added to wells of a 96-well plate, along withglutamate (10 μM) and glycine (200 nM) and various concentrations of theligand to be tested. The assay was started by the addition of 5 nM[³]MK-801 (23.9 Ci/mmol), which binds to the ion channel associated withNMDA receptors. The final volume of the assay was 200 μl. The assay wasperformed for 1 hour at room temperature. Bound radioactivity wasseparated from free by filtration, using a TOMTEC harvester. Antagonistactivity was indicated by decreasing radioactivity associated with theNMDA receptor with increasing concentration of the tested ligand.

The third binding test was operated to identify agonists by performingthe test as above, except that the concentration of glycine was 200 nM.Agonist activity was indicated by increasing radioactivity associatedwith the NMDA receptor with increasing concentration of the testedligand.

What is claimed:
 1. A compound of Formula I:

wherein: Ar₁ and Ar₂ are independently selected aryl groups, optionallysubstituted with up to five substituents independently selected from thegroup consisting of alkyl, alkoxy, cycloalkyl, cycloalkyloxy, alkanoyl,thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy,cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl,cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy,thioaryl, aralkylthio, thioaryl-alkyl, aralkylthioalkyl, halo, NO₂, CF₃,CN, OH, alkylenedioxy, SO₂NRR′, NRR′, CO₂R (where R and R′ areindependently selected from the group consisting of H and alkyl), and asecond aryl group, which may be substituted as above, wherein the arylsof the substitutions are carbocyclic; R₁ is selected from the groupconsisting of H and alkyl; R₂ is selected from the group consisting ofH, alkyl and benzyl; R₃ is selected from the group consisting of CO₂R,CONRR′, CONH(OH), COSR, SO₂NRR′, PO(OR)(OR′) and tetrazolyl, wherein Rand R′ are independently selected from the group consisting of H andalkyl; and a salt, solvate or hydrate thereof.
 2. A compound accordingto claim 1, wherein Ar₁ is an aryl group, optionally substituted with upto three substituents independently selected from halo, NO₂, CF3, CN,OH, SO₂NRR′, NRR′, CO₂R (where R and R′ are independently selected fromthe group consisting of H and alkyl), and a substituent of the formulaR″—(X)n— wherein n is 0 or 1; X is CH₂ or a heteroatom; R″ is H, alkyland aryl substituted optionally with up to three substituents selectedfrom alkyl, halo, NO₂, CF₃, CN, OH, SO₂NRR′, NRR′ and CO₂R, wherein Rand R′ are independently selected from the group consisting of H andalkyl.
 3. A compound according to claim 2, wherein Ar₁ is phenyl.
 4. Acompound according to claim 2, wherein Ar₁ is substituted phenyl.
 5. Acompound according to claim 4, wherein Ar₁ is lower alkyl substitutedphenyl.
 6. A compound according to claim 5, wherein Ar₁ is4-(alkyl)-phenyl.
 7. A compound according to claim 6, wherein said alkylgroup is selected from methyl, ethyl, n-propyl, isopropyl and n-butyl.8. A compound according to claim 1, wherein Ar₁ is alkylenedioxyphenyl.9. A compound according to claim 8, wherein Ar₁ is methylendioxyphenyl.10. A compound according to claim 9, wherein Ar₁ is3,4-methylenedioxyphenyl.
 11. A compound according to claim 1, whereinAr₁ is a benzo-fused aromatic group.
 12. A compound according to claim11, wherein Ar₁ is carbocyclic.
 13. A compound according to claim 12,wherein Ar₁ is naphthyl.
 14. A compound according to claim 13, whereinAr₁ is 2-naphthyl.
 15. A compound according to claim 1, wherein Ar₂ isan aryl group optionally substituted with up to three substituentsindependently selected from halo, haloalkyl, alkyl, haloalkoxy, andalkoxy.
 16. A compound according to claim 15 in which Ar₂ isunsubstituted aryl.
 17. A compound according to claim 16 in which Ar₂ isphenyl.
 18. A compound according to claim 15, wherein Ar₂ is substitutedphenyl.
 19. A compound according to claim 18, wherein Ar₂ ishalo-substituted phenyl.
 20. A compound according to claim 19, whereinAr₂ is phenyl substituted by chloro or fluoro.
 21. A compound accordingto claim 1, wherein R₁ is H.
 22. A compound according to claim 1,wherein R₂ is H.
 23. A compound according to claim 22, wherein R₃ ismethyl.
 24. A compound according to claim 1, wherein R₃ is COOR.
 25. Acompound according to claim 24, wherein R₃ is COOH.
 26. A compoundaccording to claim 1, selected from:N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(2-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(2,4-Difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(3-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(3-Phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,N-(5-(3,5-Bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(3,5-Diphenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-diphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-npropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-nbutylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-npentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(2-isopropylphenyl)-3-phenyl-2-penten4-yn-1-yl)-sarcosineN-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(3-Phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosineN-(3-Phenyl-5-(4-t-butylphenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-t-Butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-t-Butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-t-Butylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(3,4-Methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosineN-(5-(4-Ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine,andN-(5-(4-Propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine.27. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1, and a pharmaceuticallyacceptable carrier.
 28. A method for treating a patient having a medicalcondition for which a glycine transport inhibitor is indicated,comprising the step of ministering to the patient a pharmaceuticalcomposition as defined in claim
 27. 29. A method according to claim 28in which the medical condition is schizophrenia.
 30. A method accordingto claim 28 in which the medical condition is cognitive dysfunction. 31.A method according to claim 28 in which the medical condition isAlzheimer's disease.